US5089482A - Pharmaceutical compositions for nasal administration containing steroid hormones and dimethyl-β-cyclodextrin - Google Patents

Pharmaceutical compositions for nasal administration containing steroid hormones and dimethyl-β-cyclodextrin Download PDF

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Publication number
US5089482A
US5089482A US07/372,917 US37291789A US5089482A US 5089482 A US5089482 A US 5089482A US 37291789 A US37291789 A US 37291789A US 5089482 A US5089482 A US 5089482A
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accordance
cyclodextrin
composition
dimethyl
estradiol
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Walter A. J. J. Hermens
Franciscus W. H. M. Merkus
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • This invention relates to a pharmaceutical composition having a formulation and form suitable for nasal administration, and containing a sex hormone selected from 17 ⁇ -estradiol, progesterone, and combinations thereof.
  • 17 ⁇ -estradiol is the most active natural human oestrogen.
  • the oral administration of 17 ⁇ -estradiol is accompanied by a considerable conversion into the less active hormone estrone and subsequently into other metabolites. This conversion takes place during the absorption from the intestine and transport through the liver (first pass). This requires high dosages to achieve the effects desired as compared with parenteral administration.
  • Progesterone, too which is the most important natural human progestagen, has a very limited activity after oral administration, by reason of the metabolism in the gastro-intestinal tract and the first-pass effect of the liver.
  • the synthetic derivatives however, have an adverse stimulating effect on the protein synthesis of the liver (possibly promoting thrombosis) and exhibit a diabetogenic effect, in contrast to the natural sex hormones.
  • intranasal administration is yet proposed for both progesterone and 17 ⁇ -estradiol and esters thereof. It describes a composition for intranasal administration, comprising a solution of the sex hormones in an isotonic saline containing a surfactant, such as Tween 80, as a solubilizer.
  • a surfactant such as Tween 80
  • Adjuvants suitable for use as solubilizers are often unsuitable for the nasal mucosa and/or have an insufficient solubility increasing effect.
  • a chronic therapy with such a composition is undesirable.
  • the concentration of the natural hormone in the composition is too low, so that the dosage volume must become too high to bring about an effective therapy.
  • dimethyl- ⁇ -cyclodextrin is known per se from German patent application 3,118,218.
  • dimethyl- ⁇ -cyclodextrin it is proposed for dimethyl- ⁇ -cyclodextrin to be used for the preparation of aqueous solutions of poorly soluble, biologically active, organic compounds, such as various vitamins, steroids, protanoids, local anaesthetics, etc.
  • the combination of such substances, which include, for example, progesterone, with dimethyl- ⁇ -cyclodextrin results in the formation of intercalation complexes which are soluble in water.
  • that publication describes pharmaceutical compositions for oral or parenteral administration.
  • compositions according to the invention result in a biological availability substantially equal to that achieved with intravenous administration.
  • U.S. Pat. No. 4,596,795 teaches that the use of the dimethyl- ⁇ -cyclodextrin in sex hormone compositions for sublingual and buccal administration has virtually no effect on the absorption of the sex hormones, unlike poly- ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin. That publication, too, therefore, teaches away from the use of dimethyl- ⁇ -cyclodextrin.
  • the invention accordingly relates to pharmaceutical compositions for the nasal administration of the natural female sex hormones 17 ⁇ -estradiol and progesterone with an increased absorption of the hormones referred to by combination with the adjuvant dimethyl- ⁇ -cyclodextrin.
  • dosage forms of 17 ⁇ -estradiol and/or progesterone suitable for nasal administration are solutions, suspensions, gels and ointments.
  • the dosage forms containing the hormones referred to, either separately or in combination, can be used, for example, in treating or preventing postmenopausal conditions, such as vasomotor symptoms and osteoporosis.
  • progesterone means pregn-4-ene-3,20-dione, and comprises both progesterone obtained from natural sources and synthetic progesterone.
  • 17 ⁇ -estradiol as used herein means estra-1,3,5(10)-triene-3,17 ⁇ -diol, and includes both 17 ⁇ -estradiol obtained from a natural source and that obtained synthetically.
  • 17 ⁇ -estradiol and progesterone in combination with dimethyl- ⁇ -cyclodextrin, can be nasally administered with a biological availability substantially equal to that of intravenous administration.
  • the composition of the nasal formulations was as follows: a 0.2% 17 ⁇ -estradiol suspension in Sol. benzalkonii et hypromellosi FNA and a 0.2% 17 ⁇ -estradiol solution with 2% dimethyl- ⁇ -cyclodextrin in Sol. benzalkonii et hypromellosi FNA.
  • the i.v. formulation was a 0.1% 17 ⁇ -estradiol solution with 1% dimethyl- ⁇ -cyclodextrin in physiological saline.
  • the control vehicle (placebo) was Sol. benzalkonii et hypromellosi FNA.
  • the 17 ⁇ -estradiol serum levels were analyzed by an RIA method (Pharmacia). The results are summarized in Table 1 and FIGS. 2 and 3. ##EQU1##
  • Benzalkonii FNA and 1% progesterone solution with 8.5% dimethyl- ⁇ -cyclodextrin in Sol. benzalkonii FNA.
  • the control (placebo) was Sol. Benzalkonii FNA.
  • Blood samples were taken from a canulated femoral artery at regular time intervals. Progesterone serum levels were measured using a Coat a count® radioimmunoassay kit form DPC (Laboratorium Service, The Netherlands).
  • the formulation was administered as a nasal spray in a daily dose of 0.68 mg 17 ⁇ -estradiol, divided in 2 nasal gifts.
  • Serum 17 ⁇ -estradiol levels 10 min after nasal administration of 0.34 mg 17 ⁇ -estradiol with this formulation were in the order of 3 nmol/l. This demonstrates a rapid and good absorption of 17 ⁇ -estradiol from the described formulation. Clinical results were also encouraging. The patients decided to continue with the nasal formulation instead of oral estrogen substitution.
  • the composition for nasal administration according to the present invention may be of solid, semi-solid or liquid form. Preferably, it is an aqueous solution.
  • the concentration of 17 ⁇ -estradiol preferably ranges between 0.01% and 5% w/v and most preferably between 0.1% and 0.5% w/v.
  • the concentration of progesterone preferably ranges from 0.05% to 5% w/v, and most preferably from 0.1% to 1% w/v.
  • the concentration of dimethyl- ⁇ -cyclodextrin preferably ranges from 0.1% to 20% w/v and most preferably from 1% to 10% w/v.
  • the molar ratio of sex hormone to dimethyl- ⁇ -cyclodextrin preferably ranges from 1:6 to 4:1, and most preferably from 1:2 to 2:1.
  • the pH of the composition can be adjusted by adding an acid, base or buffer solution during preparation.
  • the pH preferably ranges from 6 to 8.
  • Preservatives such as benzalkonium chloride
  • Swelling agents such as cellulose derivatives, can be incorporated in the composition to form nasal gels.
  • the solution can be autoclaved or sterilized by means of 0.2 ⁇ m membrane filtration.
  • compositions are highly patient-friendly, which is especially important in long-term therapy.
  • Dimethyl- ⁇ -cyclodextrin is tasteless, odourless, low-toxic and little irritating to the nasal mucous membrane in the concentrations used in the composition, and accordingly is safe in long-term use.
  • composition has no significant effect on ciliary movement in vitro, which is important, because an inhibition of ciliary movement affects the nasal defence mechanism.
  • compositions according to the present invention can be prepared by dissolving 17 ⁇ -estradiol and/or progesterone together with dimethyl- ⁇ -cyclodextrin in 96% alcohol, followed by evaporation at 40° C. under an N 2 stream.
  • the dry residue can be dissolved in an aqueous medium, such as Sol.
  • Benzalkonii FNA whereafter, for example, sodium chloride can be added to achieve isotony.
  • progesterone was combined with 2.12 g dimethyl- ⁇ -cyclodextrin and 0.45 g sodium chloride. The total volume was made up to 50 ml with Solutio benzalkonii FNA (containing 0.01% benzalkonium chloride and 0.1% sodium edetate).
  • a suitable dose of the above compositions can be 0.05 ml to 0.2 ml for a single dose and 0.05 ml to 0.8 ml per 24 hours.
  • compositions according to the invention are not limited to the above examples.
  • the scope of the invention is only determined by the claims.
  • FIG. 1 shows the effect of 17 ⁇ -estradiol compositions on the nasal ciliary frequency in vitro.
  • 17 ⁇ -estradiol 0.01%
  • polysorbate 80 2%
  • 17 ⁇ -estradiol 0.1%) in dimethyl- ⁇ -cyclodextrin (1%), Locke Ringer (control), ⁇ ciliary tissue washed in Locke Ringer.
  • FIG. 3 shows the surfaces (AUCs) under the serum concentration-time curves after nasal and i.v. administration of 17 ⁇ -estradiol.
  • Left axis absolute (ng.min/ml).
  • control placebo

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US07/372,917 1988-07-01 1989-06-28 Pharmaceutical compositions for nasal administration containing steroid hormones and dimethyl-β-cyclodextrin Expired - Lifetime US5089482A (en)

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NL8801670A NL8801670A (nl) 1988-07-01 1988-07-01 Farmaceutisch preparaat.

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EP (1) EP0349091B1 (fr)
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Cited By (27)

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US5206224A (en) * 1989-10-18 1993-04-27 Kabushikikaisha Ueno Seiyaku Oyo Kenkyujo Treatment of male hormone related diseases by cyclodextrins and their derivatives
WO1996016659A1 (fr) * 1994-11-30 1996-06-06 Pharmos Corp. Cyclodextrines utilisees comme agents de suspension dans des suspensions pahramaceutiques
US5540930A (en) * 1993-10-25 1996-07-30 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
AU675307B2 (en) * 1993-03-26 1997-01-30 Les Laboratoires Servier Nasal pharmaceutical composition containing a progestational agent
US5624940A (en) * 1993-12-14 1997-04-29 Eli Lilly And Company Aqueous solution inclusion complexes of benzothiophene compounds with water soluble cyclodextrins, and pharmaceutical formulations and methods thereof
US5668097A (en) * 1994-08-12 1997-09-16 The Procter & Gamble Company Uncomplexed cyclodextrin solutions for odor control on inanimate surfaces
US5861431A (en) * 1995-06-07 1999-01-19 Iotek, Inc. Incontinence treatment
US5883087A (en) * 1991-01-07 1999-03-16 Pherin Corporation Androstane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods
US5942501A (en) * 1996-08-16 1999-08-24 Collaborative Laboratories, Inc. Cyclodextrin derivative complex
US5977070A (en) * 1992-07-14 1999-11-02 Piazza; Christin Teresa Pharmaceutical compositions for the nasal delivery of compounds useful for the treatment of osteoporosis
US20030207855A1 (en) * 2000-03-10 2003-11-06 Hill Edward N. Novel estrogenic compounds
US20040022738A1 (en) * 2002-08-02 2004-02-05 Pike Malcolm C. Nasal spray steroid formulation and method
US20040022739A1 (en) * 2002-08-02 2004-02-05 Daniels John R. Nasal spray formulation and method
US20040023867A1 (en) * 2002-08-02 2004-02-05 Anna-Marie Daniels Methods and compositions for treating benign gynecological disorders
WO2004012712A1 (fr) * 2002-08-02 2004-02-12 Balance Pharmaceuticals, Inc. Methodes et compositions servant au traitement des troubles gynecologiques benins, a la contraception et a l'hormonotherapie de substitution
US20040198670A1 (en) * 2003-04-04 2004-10-07 Hill Edward N. Novel estrogenic compounds
US20040259851A1 (en) * 2003-04-11 2004-12-23 Leonard Thomas W. Methods of administering estrogens and progestins
US6855703B1 (en) 2000-03-10 2005-02-15 Endeavor Pharmaceuticals Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds
US20050043343A1 (en) * 2003-07-28 2005-02-24 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor
US20050153946A1 (en) * 2003-12-24 2005-07-14 Collegium Pharmaceuticals, Inc. Temperature-stable formulations, and methods of development thereof
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US20060045850A1 (en) * 2004-08-30 2006-03-02 Qpharma, Llc Nasal delivery of cyclodextrin complexes of anti-inflammatory steroids
US20060183724A1 (en) * 2005-02-03 2006-08-17 Diliberti Charles E Compositions of unconjugated estrogens and methods for their use
US20070142307A1 (en) * 2000-03-10 2007-06-21 Barr Laboratories, Inc. Novel estrogenic compounds
US20090215735A1 (en) * 2002-02-25 2009-08-27 Alcon, Inc. Topical solution formulations containing a corticosteroid and a cyclodextrin
US20100234330A1 (en) * 2003-07-23 2010-09-16 Hill Edward N Novel Estrogenic Compounds
WO2013052889A1 (fr) * 2011-10-07 2013-04-11 Florida State University Research Foundation Mécanisme d'administration nasale pour une utilisation prophylactique et en phase post-aiguë pour de la progestérone et/ou son énantiomère destiné à être utilisé dans le traitement de lésions cérébrales traumatiques légères

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DE4207922A1 (de) * 1992-03-13 1993-09-23 Pharmatech Gmbh Wasserloesliche einschlussverbindungen und verfahren zu deren herstellung
DE4214953C2 (de) * 1992-05-06 1995-05-18 Arrowdean Ltd Arzneimittel zur Erhöhung des Testosteronspiegels
DE4227569C1 (de) * 1992-08-20 1994-06-09 Inst Chemo Biosensorik Verfahren zum empfindlichen enzymatischen Nachweis von anorganischem Phosphat
US6066627A (en) * 1994-08-04 2000-05-23 Pherin Corporation Steroids as neurochemical initiators of change in human blood levels of LH
US5679573A (en) * 1995-07-27 1997-10-21 Abbott Laboratories Stabilized aqueous steroid immunoassay standards with cyclodextrins
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FR2784584B1 (fr) * 1998-10-14 2002-09-20 Adir Procede de preparation d'une solution pour pulverisation nasale contenant une ou plusieurs hormones sexuelles et une cyclodextrine
FR2791572A1 (fr) * 1999-03-31 2000-10-06 Adir Utilisation d'hormones sexuelles pour l'obtention d'une composition pharmaceutique nasale utile pour le traitement des saignements uterins indesirables
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AR086400A1 (es) 2011-05-13 2013-12-11 Trimel Pharmaceuticals Corp Formulaciones en gel intranasal de testosterona en dosis de menor potencia y uso de las mismas para el tratamiento de la anorgasmia o el trastorno de deseo sexual hipoactivo
GB201200062D0 (en) 2012-01-04 2012-02-15 Innotesto Bvba Estradiol oromucosal liquid compositions
US11744838B2 (en) 2013-03-15 2023-09-05 Acerus Biopharma Inc. Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event

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DE10199066I1 (de) 2002-02-21
EP0349091A1 (fr) 1990-01-03

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